cabazitaxel

Action

As a microtubule inhibitor, cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions.

Availability

Injection: 60 mg/1.5 ml in single-use vial

Indications and dosages

➣ Metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing treatment regimen

Adults: 25 mg/m² I.V. by 1-hour infusion q 3 weeks in combination with prednisone 10 mg P.O. daily throughout treatment

Dosage adjustment

• Grade 3 or greater neutropenia for longer than 1 week despite appropriate treatment, including granulocytecolony stimulating factor (G-CSF)

• Febrile neutropenia

• Grade 3 or greater diarrhea or persisting diarrhea despite appropriate treatment

Contraindications

• Hypersensitivity to drug or to other drugs formulated with polysorbate 80

• Patients with neutrophil counts of 1,500 cells/mm³ or less

Precautions

Use cautiously in:

• hepatic impairment with total bilirubin at or above the upper limit of normal (ULN), or AST or ALT levels 1.5 × ULN or greater (avoid use)

• severe renal impairment (creatinine clearance less than 30 mL/minute) and end-stage renal disease

• neutropenia

• GI symptoms

• infusion reactions

• concurrent use of strong CYP3A inducers or inhibitors (avoid use)

• elderly patients

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Follow facility policy for handling, preparing, and administering carcinogenic, mutagenic, and teratogenic drugs.

See Don't administer by I.V. push or bolus.

• Premedicate patient at least 30 minutes before each dose with the following I.V. drugs to reduce risk or severity of hypersensitivity: Antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg, or equivalent antihistamine), corticosteroid (dexamethasone 8 mg or equivalent steroid), H₂ antagonist (ranitidine 50 mg or equivalent H₂ antagonist).

• Give oral or I.V. antiemetic prophylaxis as needed.

• Don't use PVC infusion containers or polyurethane infusion sets for preparation or administration of drug.

• Be aware that drug requires two dilutions before administering.

• To reconstitute, use entire contents of accompanying diluent to achieve a concentration of 10 mg/ml. Withdraw only required amount of first dilution to prepare final infusion solution before administering. When transferring diluent, direct needle onto inside wall of vial and inject slowly to limit foaming. Remove syringe and needle and gently mix initial diluted solution by repeated inversions for at least 45 seconds to ensure full mixing of drug and diluent. Don't shake. Let solution stand for a few minutes to allow foam to dissipate; check that solution is homogeneous and contains no visible particulate matter.

• The second dilution should be done immediately (within 30 minutes) to obtain final infusion. Withdraw recommended dose from vial containing 10 mg/ml using calibrated syringe and further dilute into sterile 250-ml PVC-free container of either normal saline solution or 5% dextrose solution for infusion. If dose greater than 65 mg is required, use larger volume of infusion vehicle so that a concentration of 0.26 mg/ml isn't exceeded. Concentration of final infusion solution should be between 0.10 and 0.26 mg/ml. Remove syringe and thoroughly mix final infusion solution by gently inverting bag or bottle. Final infusion solution in either normal saline solution or 5% dextrose solution should be used within 8 hours if kept at ambient temperature (including the 1-hour infusion) or within a total of 24 hours if refrigerated (including the 1-hour infusion).

• Inspect visually for particulate matter, crystals, and discoloration before administering. Discard unused portion.

• Discard first diluted solution or second (final) infusion solution if either isn't clear or appears to have precipitation.

• As final infusion solution is supersaturated, it may crystallize over time. If this occurs, don't use solution; discard it.

• Don't mix with other drugs.

• Use an in-line filter of 0.22-micrometer nominal pore size for administration.

See Reduce dosage as prescribed for Grade 3 or greater neutropenia lasting longer than 1 week despite appropriate treatment (including G-CSF), for febrile neutropenia, or for Grade 3 or greater diarrhea or persisting diarrhea despite appropriate treatment. Discontinue drug if patient continues to experience any of these reactions at prescribed lower dosage.

• Consider G-CSF and secondary prophylaxis in all patients considered to be at increased risk for neutropenia complications.

See Immediately discontinue infusion if severe hypersensitivity reactions occur and initiate appropriate therapy. Be aware that patients with a history of severe hypersensitivity reactions shouldn't be rechallenged with this drug.

Adverse reactions

CNS: headache, dizziness, asthenia, fatigue, peripheral neuropathy

CV: hypotension, arrhythmia

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, anorexia, dyspepsia, mucosal inflammation

GU: hematuria, urinary tract infection, dysuria, renal failure

Hematologic: neutropenia, anemia, leukopenia, thrombocytopenia

Musculoskeletal: back pain, arthralgia, muscle spasms

Respiratory: dyspnea, cough

Skin: alopecia

Other: pyrexia, dysgeusia, pain, weight loss, dehydration, peripheral edema,

hypersensitivity

Interactions

Drug-drug. Strong CYP3A inducers (such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentin): decreased cabazitaxel concentration

Strong CYP3A inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): increased cabazitaxel concentration

Drug-diagnostic tests. ALT, AST, bilirubin: increased levels

Drug-herbs. St. John's wort: decreased cabazitaxel concentration

Patient monitoring

• Monitor CBC with differential and renal and hepatic function tests closely.

• Be aware that the incidence of Grade 3 to 4 hematologic adverse reactions, particularly neutropenia and febrile neutropenia, is higher in patients age 65 or older compared to younger patients.

See Be aware that cabazitaxel is extensively metabolized in the liver and hepatic impairment is likely to increase cabazitaxel concentration, with risk of severe and life-threatening complications in patients receiving other drugs belonging to same class.

See Continue to closely monitor patents for hypersensitivity reactions, especially during first and second infusions. Hypersensitivity reactions may occur within a few minutes after initiation of infusion; therefore, have facilities and equipment available for treatment of hypotension and bronchospasm. If severe hypersensitivity occurs that includes generalized rash, erythema, hypotension, and bronchospasm, immediately discontinue infusion and initiate appropriate therapy.

• Watch for dehydration if patient has nausea, vomiting, or severe diarrhea; be aware that intensive measures may be required for severe diarrhea and electrolyte imbalance. Initite appropriate measures, including rehydration and antidiarrheal or antiemetic medications, as needed. Delay or reduce dosage as necessary if patient has diarrhea at or above Grade 3.

See Be aware that renal failure may occur in association with sepsis, dehydration, or obstructive uropathy. Immediately take appropriate measures to identify causes of renal failure and treat aggressively.

Patient teaching

• Explain the importance of taking oral prednisone as prescribed.

• Explain the importance of routine blood cell counts and instruct patient to monitor temperature frequently.

See Instruct patient to immediately contact prescriber if signs and symptoms of hypersensitivity reactions occur, including rash or itching, skin redness, dizziness or faintness, chest or throat tightness, facial swelling, or breathing problems.

See Instruct patient to immediately contact prescriber if urinary tract problems, irregular heartbeat, significant vomiting or diarrhea, decreased urinary output, or blood in urine occurs.

• Advise patient to report numbness or tingling of the hands or feet or muscle problems.

• Advise patient to contact prescriber if a fever or other evidence of potential infection, such as cough or pain on urination, develops.

• Instruct patient to tell prescriber all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with cabazitaxel.

• Advise patient not to use St. John's wort without consulting prescriber.

• Advise female patient of childbearing age to avoid becoming pregnant while receiving this drug.

• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.